Cladribine and progressive MS
`Clinical and MRI outcomesof a multicenter controlled trial
`
`George P.A. Rice, MD, for the Cladribine Clinical Study Group*; and Massimo Filippi, MD,
`and Giancarlo Comi, MD, for the Cladribine MRI Study Group*
`
`
`
`Article abstract—Objective: To evaluate the safety and efficacy of two doses of cladribine in patients with progressive
`MS. Background: Treatment of progressive MS patients with cladribine in a previous single-center, placebo-controlled
`clinical trial was associated with disease stabilization. Methods: In the current study, 159 patients with a median baseline
`Kurtzke’s Expanded Disability Status Scale (EDSS)score of 6.0 were randomly assigned to receive placebo or cladribine
`0.07 mg/kg/day for 5 consecutive days every 4 weeks for either two or six cycles (total dose, 0.7 mg/kg or 2.1 mg/kg,
`respectively), followed by placebo, for a total of eight cycles. Thirty percent had primary progressive MS (PPMS) and 70%
`had secondary progressive MS (SPMS). EDSS and Scripps Neurologic Rating Scale (SNRS) scores were assessed bi-
`monthly and MRI was performed every 6 months. The primary outcome measure wasdisability (mean change in EDSS).
`Results: Mean changesin disability did not differ among the groupsat the end of the 12-month double-blind phase. Both
`cladribine treatments were superior to placebo for the proportion of patients having gadolinium-enhanced T1 lesions and
`for the mean volume and numberof such lesions (p = 0.003). Differences were statistically significant at the 6-month
`evaluation time, with =90% reduction in volume and numberof enhanced T1 lesions, which was maintained through final
`evaluation. This effect segregated largely with the SPMSgroup. The T2 burden of disease showed a modest improvement
`in cladribine-treated patients and worsened in placebo-treated patients. Most adverse events were mild or moderate in
`severity and not treatment limiting. Conclusion: No significant treatment effects were found for cladribine in terms of
`changes in EDSS or SNRSscores. Both dosesof cladribine produced and sustained significant reductions in the presence,
`number, and volumeof gadolinium-enhanced T1 brain lesions on MRI, and cladribine 2.1 mg/kg reduced the accumulation
`of T2 lesion load. Cladribine at doses up to 2.1 mg/kg was generally safe and well tolerated. Key words: Cladribine—
`MRI—Progressive MS—Suppressionof disease activity.
`NEUROLOGY 2000;54:1145-1155
`
`
`With the exception of trauma, MS—a demyelinating
`disease of the CNS with an estimated prevalence of
`250,000 to 350,000 in the United States and 1.1 mil-
`lion worldwide—is the most commoncauseof neuro-
`logic disability in young adults.1 About two thirds of
`patients develop a relapsing-remitting pattern
`(RRMS), and the majority of these will experience a
`progressive deterioration, or secondary progressive
`MS (SPMS); about 15% of patients appear to have a
`progressive course from onset, or primary progres-
`sive MS (PPMS).? The mandate for prevention ofdis-
`ease progression is compelling. The natural history of
`progressive MS has been little altered, at least in the
`short term, by currently available agents. B-Interferons
`have been reported to be effective in the treatment of
`RRMS,?"8 and recently, interferon B-1b has been re-
`ported to delay the time to confirmed progression in
`patients with SPMSby 9 to 12 months."
`MRI hasallowed direct visualization of the num-
`ber, location, and volume of acute and chronic lesions
`associated with underlying disease pathology, and
`
`somecorrelations between MRI andclinical parame-
`ters have been demonstrated.% In patients with
`RRMSand SPMS,there is a correlation between the
`frequency and extent of lesion enhancement and
`short-term disease activity.1*9 In clinical trials, the
`presence of contrast-enhanced T1 lesions at baseline
`has been shown to predict both clinical and MRI
`activity in the following 6 months,’ and, in patients
`with clinically isolated syndromes suggestive of MS,
`T2 lesion load at presentation is strongly correlated
`with disability after 5 years.2°?! A recent meta-
`analysis of data from nine studies in 307 patients
`with RRMS and SPMS, however, found that although
`enhancement predicts the occurrence of relapses it is
`not a strong predictor of subsequent accumulation of
`disability over a 2-year period of observation.22 Phase
`ITI clinical trials evaluating new therapies for MS now
`almost always include MRIevaluations along with tra-
`ditional clinical assessments.'53
`Cladribine (2-chlorodeoxyadenosine; 2-CdA) is a
`purine nucleoside analogue resistant to the action of
`
`*See Appendix 1 on page 1154 for a listing of membersof the Cladribine Study Group and the Cladribine MRI Study Group.
`From the University Hospital (Dr. Rice), University of Western Ontario, London, Canada; and the Neuroimaging Research Unit (Dr. Filippi) and Clinical
`Trials Unit (Dr. Comi), Department of Neuroscience, Scientific Institute Ospedale San Raffaele, University of Milan, Italy.
`Supported by the R.W. Johnson Pharmaceutical Corporation, Raritan, NJ.
`Presented in part at the 49th annual meeting of the American Academy of Neurology; Boston, MA; April 1997; and at the 51st annual meeting of the
`American Academy of Neurology; Toronto, Ontario, Canada; April 1999.
`Received June 10, 1999, Accepted in final form November 1, 1999.
`Address correspondence and reprint requests to Dr. Rice, LHSC-UC, 339 Windermere Road, London, Ontario N6A 5A5, Canada; e-mail: grice@julian.uwo.ca
`
`Copyright © 2000 by the American Academy of Neurology 1145
`
`Hopewell EX1018
`
`Hopewell EX1018
`
`1
`
`

`

`adenosine deaminase, which results in preferential
`lymphocytotoxicity. In cells with a high ratio of deoxy-
`cytidine kinase to deoxynucleotidase (e.g., lymphocytes
`and monocytes), cladribine is phosphorylated into the
`active triphosphate deoxynucleotide, 2-CdATP,
`which accumulates, causing a disruption of cellular
`metabolism, DNA damage, and subsequent cell
`death.™ Its long-lasting lymphocytotoxic activity sug-
`gests that cladribine could be useful in modulating
`autoimmuneprocesses involving lymphocyte abnor-
`malities such as MS. Sipe and colleagues have re-
`ported the outcome of a placebo-controlled clinical
`trial of cladribine in patients with progressive
`MS.7526 Treatment with a total dose of 2.8 mg/kg
`cladribine was associated with significant stabiliza-
`tion of the disease in patients with SPMS. Compared
`with a progression rate of 50% of the patients treated
`with placebo, 95% of cladribine-treated patients were
`stable at 1 year. These clinical observations were
`supported by favorable effects in the MRI brain
`scans, i.e., nearly complete elimination of enhanced
`T1 lesions and stabilization of T2 lesion volume at
`final evaluation. Encouraged by this single-center
`study, a multicenter, double-blind, placebo-controlled
`trial was conducted to evaluate the safety and effi-
`cacy of two doses of cladribine in patients with pro-
`gressive MS.
`
`Methods. Study population. A total of 159 patients
`with progressive MS were enrolled at six clinical centers in
`the United States and Canada. Inclusion criteria for entry
`into the trial were clinically definite or laboratory-
`supported MS according to the Schumachercriteria?’ or
`Poser criteria”® and defined as chronic progressive by the
`slow progression of signs and symptomsover the preceding
`12 months; a baseline Expanded Disability Status Scale
`(EDSS)*® score between 3.0 and 6.5; age 21 to 60 years;
`serum creatinine levels <1.5 mg/dL and creatinine clear-
`ance = 80% of age-adjusted normal value; aspartate and
`alanine transaminase (AST and ALT) and alkaline phos-
`phatase levels less than twice the normal upperlimit; neu-
`trophil count >1600/u.L and platelet count >1380,000/.L;
`andclinically normal ECG andchest x-ray. Patients were
`excluded from thetrial if there was significant history of
`medical disease within the preceding 2 years that would
`impair participation in the trial; use of corticosteroids or
`other immunosuppressants such as cyclophosphamide,
`azathioprine, cyclosporine, or B-interferon within the pre-
`ceding 3 months; total lymphoid irradiation; persistent
`leukopenia or thrombocytopenia after treatment with im-
`munosuppressive agents; history of alcohol or drug abuse
`within the preceding year or of attempted suicide; malig-
`nancy or history of malignancy within the preceding 5
`years; pregnancy or nursing; positive test result for HIV;
`use of an experimental drug or device within the preceding
`60 days; or prior participation in a trial with cladribine.
`The protocol was approved by therespective institutional
`review boards, and patients signed informed consent
`forms.
`Study design. This multicenter trial was a random-
`ized, double-blind, parallel-group, placebo-controlled study
`designed to compare the safety and efficacy of two doses of
`1146 NEUROLOGY 54 March(1 of 2) 2000
`
`cladribine and placebo administered by subcutaneous (SC)
`injection in patients with progressive MS, to evaluate the
`dose-response relationship, and to obtain information con-
`cerning the duration of any effects. The study included a
`4-week screening phase, a 1-year double-blind phase, and
`a 6-year long-term extension. Patients were assigned to
`one of three parallel treatment groups (cladribine, 2.1 mg/
`kg; cladribine, 0.7 mg/kg; or placebo) according to a
`computer-generated randomization schedule stratified by
`baseline disease severity and site. Sample size computa-
`tion was based on an assumed SD of 1.7 for change from
`the baseline EDSS score. The planned sample size of 50
`patients per treatment group would have a statistical
`powerof 80% based on a two-sided alpha of 0.05 to detect a
`difference of 1.0 in change from the baseline EDSS score
`betweenthe cladribine, 2.1 mg/kg, and placebo groups.
`The trial was initiated in December 1994. During the
`1-year double-blind phase, patients were evaluated
`monthly for vital signs, adverse events, and a complete
`blood count (CBC) that was obtained just before the
`monthly visit. Neurologic status was evaluated bimonthly
`by assessment of EDSS and Scripps Neurologic Rating
`Scale (SNRS) scores by the blinded clinical investigators,
`who underwent standardized training. Brain MRI scans
`were obtained at baseline and months 6 and 12, as were
`total lymphocyte count and lymphocyte subset counts
`(CD3*, CD4*, CD8*, CD19*, CD16* plus CD56*, and
`CD4*/CD8" ratio). Physical examinations were performed
`at baseline and months4, 8, and 12; a chemistry panel and
`urinalysis were performed periodically, and an ECG was
`obtained at the end of the treatment phase. During the
`first year of the post-double-blind follow-up phase, EDSS
`scores, CBC, and lymphocyte counts were assessed quar-
`terly; MRI scans were obtained at months 18 and 24.
`In addition to the treating physician, an examining phy-
`sician was designated at each site to assess the patient’s
`neurologic function using EDSS and SNRSscoring. All
`study investigators and patients were blinded to treatment
`assignment; adverse events and unblinded hematology re-
`sults were routinely reviewed by an independent safety
`monitoring board. After all patients at a study site com-
`pleted the 12-month double-blind phase, the blind was bro-
`ken, and patients who fulfilled the hematologic dosing
`criteria were permitted to receive open-label cladribine
`treatment during the long-term extension phase of the
`study, provided at least 12 months had elapsed since the
`last dose of cladribine and there was evidence of disease
`progression. Patients treated with open-label cladribine
`were evaluated monthly for 12 months followinginitiation
`of the drug, and then quarterly.
`Study medications and dosage. Patients who met the
`protocol-specified entry criteria were randomized in ap-
`proximately equal numbers to receive eight monthly
`courses of therapy. Patients received six courses of cladri-
`bine 0.07 mg/kg/day SC for 5 consecutive days (total dose,
`2.1 mg/kg), followed by two courses of placebo or two
`courses of cladribine 0.07 mg/kg/day SC for 5 consecutive
`days (total dose, 0.7 mg/kg), followed by six courses of
`placebo or eight courses of placebo SC for 5 consecutive
`days. To receive a subsequent course of blinded study
`drug, patients were required to meet the hematologic crite-
`ria, which were based on the results of a CBC obtained 2 to
`4 days before each dosing period and are listed in Appen-
`
`2
`
`

`

`starting point. The program then traces a contour from the
`dix 2. For a patient who did not meet these criteria, pla-
`most recent point, following the same principle described
`cebo was substituted for the active drug for that dosing
`above; the contour is complete when it traces back to the
`period. If the hematologic criteria for dosing were met at
`starting point. The MSlesions detected are recorded in a
`the next evaluation, the patient received active drug the
`file as regions of interest (ROIs) and superimposed on each
`following month, up to the eighth month. All CBC data
`image slice. The program automatically calculates the sin-
`were reviewed by an independentthird party. Thetreat-
`gle ROI area. Manual outlining is required to modify part
`ing physician remained blinded but was provided with
`of the boundary of poorly defined lesions or (more rarely)
`any abnormal CBC results required for proper medical
`to fully outline lesions not definable by contouring. The
`management.
`total lesion volumeis then calculated, multiplying the total
`Concomitant therapy. Methylprednisolone, 1 g/day for
`ROI area by theslice thickness. For the whole measure-
`up to 5 days, was allowed only for treatment of severe
`ment process, the technicians followed recently published
`exacerbations. In addition, patients were allowed to con-
`guidelines.*!
`tinue receiving symptomatic therapies to treat trouble-
`Statistical analyses. Efficacy and safety analyses were
`some symptoms of MS (e.g., baclofen for spasticity or
`based on the population of patients who received at least
`oxybutynin chloride for bladder dysfunction).
`one dose of study medication and had available data. For
`MRIevaluation. Dual-echo conventional spin-echo im-
`efficacy variables, all hypothesis tests were carried out
`ages were obtained using repetition times of 2500 msec
`two-sided, with a significance level of <0.05 considered to
`and echo timesof 30 (proton-density weighting) and 90 (T2
`be statistically significant.
`weighting) msec. T1-weighted images were obtained using
`The designated primary efficacy parameter was mean
`repetition times of 600 msec and echo times of 20 msec.
`change in EDSSscore from baseline to the final evalua-
`For both sequences,slices were axial with a matrix size of
`tion. Secondary clinical outcome measures were mean
`256 X 256 mm andafield of view of 200 X 200 mm.
`change from baseline in SNRSscore and timeto progres-
`Sections were 4 mm thick with a 1-mm interslice gap for
`sion of MS. Disease progression was defined as an increase
`the dual-echo scans and 3 mm thick and contiguous for the
`in EDSSscore of =1.0 for patients with a baseline disabil-
`T1-weighted scans. The total imaging time was approxi-
`ity of 3.0 to 5.0 and an increase in EDSSscore of =0.5 for
`mately 20 to 25 minutes. Special attention was given to
`patients with a baseline disability of 5.5 to 6.5, which was
`careful repositioning of the patient, using laser guidance
`confirmed at the next scheduled visit. EDSS and SNRS
`and external landmarksto help achieve reproducible slice
`examinations were performed by the blinded examining
`positions. All scan data were blinded to treatment, date,
`physician every second month during the double-blind
`and sequenceof scan.
`phase. Treatmentdifferences for the change from baseline
`Lesion identification. Postcontrast T1-weighted images.
`to the final evaluation for these variables were assessed
`A single experienced observer identified enhancedlesions fol-
`using a Wilcoxon’s rank sum test. Comparisons were made
`lowing rules and criteria established in recently published
`between the placebo and cladribine 2.1 mg/kg groups and
`guidelines.® Areas of enhancement were marked on trans-
`the placebo and cladribine 0.7 mg/kg groups, respectively.
`parent sheets superimposed over the scan hard copies, and
`Time to progression of MS was analyzed using survival
`then the total number of enhanced lesions per scan was
`analysis methods. Kaplan-Meier estimates for the proba-
`counted. Corresponding dual-echo images were used to in-
`bilities of failure were computed for each group. Log-rank
`crease the confidence in lesion detection.
`tests were used to compare the distributions between the
`T2-weighted images. A single experienced observer
`placebo and cladribine 2.1 mg/kg groups and between the
`identified hyperintense MS lesions and markedthecorre-
`placebo and cladribine 0.7 mg/kg groups.
`sponding areas on transparent sheets superimposed over
`The evaluation of MRI efficacy is based on the propor-
`the proton-density scan hard copies. Corresponding T2-
`tion of patients with contrast-enhanced T1-weighted brain
`weighted images were used to increase the confidence in
`lesions at the final evaluation. Additional MRI efficacy
`lesion detection.
`assessments are based on the number and volumeof en-
`Lesion segmentation and measurement of lesion volume.
`hanced T1-weighted lesions and volume of T2-weighted
`Trained technicians measured the lesion volumes for the
`lesions. Comparisons between treatment groups (placebo
`scans belonging to the same patient to avoid variabilities
`versus cladribine 2.1 mg/kg, placebo versus cladribine 0.7
`of interobserver measurement. A local thresholding tech-
`mg/kg) of the proportion of patients with enhanced T1
`nique was used for lesion segmentation on computer-
`lesions at months 6 and 12 and thefinal evaluation were
`displayed images, with the marked hard copies kept as a
`made using Fisher’s exact test. Treatment differences in
`reference. This local thresholding technique for segmenta-
`enhanced T1 lesion volume and number, T2 lesion volume,
`tion was provided by the Dispunc display software for MR
`and change and percent change in T2 lesion volume from
`images, developed by David Plummer (University College,
`baseline to final evaluation were assessed using Wilcoxon’s
`London, UK). The observer first chooses a point on the
`rank sum test.
`lesion using a mouse-controlled cursor, and the algorithm
`Safety analyses included summaries of adverse events.
`starts contouring, following from the strongest edge point
`For laboratory analytes, vital signs, and body weights,
`in the neighborhood of the user-selected point. This stron-
`means and mean changes from baseline were computed at
`gest edge point(i.e., the starting point) is found by search-
`each monthlyvisit.
`ing over a 5 X 5 pixel square area with the manually
`selected point in its center. Once the algorithm has found
`the starting point, the program, searchingin all directions
`and choosing the strongest one, finds the next contour
`point, which must haveat least as strong a gradient as the
`
`Results. Demographic and baseline characteristics.
`The 159 eligible patients were randomly assigned to re-
`ceive placebo (n = 54), cladribine 0.7 mg/kg (n = 53), or
`cladribine 2.1 mg/kg (n = 52). The three treatment groups
`March(1 of 2) 2000 NEUROLOGY 54 1147
`
`3
`
`

`

`All patients in study
`Sei
`0.500
`Cladribine Cladribine
`
`Placebo Cladribine 0.7=Cladribine 2.1
`Placebo 0.7 mg/kg
`2.1 mg/kg
`(n=54)
`(n=53}
`(n=52)
`
` Characteristic (n = 54) (n = 53) (n = 52)
`
`
`29% (15)
`300
`
`0.375
`
`Progressed
`25th percentile
`
`26% (14)
`344
`
`2B% (15)
`302
`
`Table 1 Demographic and baseline characteristics
`
`Age, mean (y)
`% Male/female
`
`Pattern of disease
`
`% PPMS
`
`% SPMS
`
`Duration of disease (y)
`Mean
`
`Median
`
`EDSSscore at entry
`Mean
`
`Median
`
`44.2
`37/63
`
`44.6
`42/58
`
`43.8
`50/50
`
`26
`
`74
`
`12.3
`
`11.7
`
`5.6
`
`6.0
`
`36
`
`64
`
`10.9
`
`10.0
`
`5.6
`
`6.0
`
`29
`
`71
`
`10.6
`
`8.8
`
`5.6
`
`6.0
`
`60.9
`
`60.7
`
`62.3
`
`25/75
`30/70
`31/69
`Category, %3.0-5.0/5.5-6.5
`Placebo Cladribina 0.7=Cladribine 2.1
`
`SNRSscore at entry
`(n=40)
`(n=34)
`(n=37)
`Mean
`33% (13)
`24% (8)
`27% (10)
`300
`273
`
`& s &
`&
`Days From Baseline
`
`we
`
`&
`
`we
`
`Patients with SPMS
`
`Progressed
`25th percentile
`
`ProbabilityofProgression°ooiS&aS 0.0
`ProbabilityofProgression
`
`
`
`62.0 62.0Median 62.0
`
`
`
`
`
`PPMS = primary progressive MS; SPMS = secondary progres-
`sive MS; EDSS = Expanded Disability Status Scale; SNRS =
`Scripps Neurological Rating Scale.
`
`were similar with respect to age, gender, duration and
`pattern of disease, and baseline disability as defined by
`EDSS or SNRSscores (table 1). Overall, the median age
`was 44 years; 43% of patients were men and 57% were
`women. At baseline, 111 (70%) patients had SPMS and 48
`(30%) patients had PPMS; 71% of patients had a baseline
`EDSS score of =5.5, indicating a population with substan-
`tial disability. Consistent with a population of more ad-
`vanced disease and 30% of patients with PPMS, 63% had
`no enhanced lesions at baseline. Mean enhanced T1 lesion
`
`count was 1.3, and mean enhanced T1 lesion volume was
`216.4 »L at baseline. Mean T2 lesion volume at baseline
`was 12.0 mL. Patients in the placebo group had a some-
`what smaller mean enhanced T1 lesion volume than pa-
`tients in the two cladribine groups (p = NS), and T1 lesion
`volumes at baseline had higher standard deviations among
`the cladribine patients than amongtheplacebopatients.
`Compliance. All 159 patients randomized to receive
`double-blind therapy received at least one dose of the
`study drug, and all are included in the efficacy analysis;
`155 (97%) patients completed the double-blind phase.
`There were no withdrawals due to adverse events; 4 (3%)
`patients withdrew voluntarily from the study (subject
`choice) before completion of the double-blind phase (three
`from the low-dose cladribine group and one from the
`higher-dose group). The majority of patients received all
`eight scheduled courses of therapy (7/54 placebo-treated
`patients, 11/53 cladribine 0.7 mg/kg-treated patients, and
`16/52 of 2.1 mg/kg-treated patients received a placebo sub-
`stitution). The most common reasons forfailure of the dos-
`ing criteria were fluctuations in hemoglobin levels and
`platelet counts, which occurred at a similar frequency in
`all groups.
`Post-double-blind follow-up data are available for 148 of
`the 159 patients enrolled in the double-blind phaseofthis
`1148 NEUROLOGY 54 March(1 of 2) 2000
`
`Days From Baseline
`
`Figure 1. Probability of disease progression over time. SP
`= secondary progressive.
`
`ongoing study. For the outcomes presented here, the mean
`duration of follow-up from thefirst dose was 29 months.
`Clinical outcomes. During the 12-month double-blind
`phase, the mean changes in EDSS and SNRSscores from
`baseline to final evaluation were small in all three treat-
`ment arms (placebo, 0.7 mg/kg, and 2.1 mg/kg cladribine),
`and no differences among treatment groups were observed
`for placebo and cladribine. Examination of changes in
`EDSSscores according to pattern of disease showed that
`for patients with SPMS, EDSS scores increased modestly
`(0.3) over time in the placebo group but less in the active
`treatment groups (+0.0, p = NS); by comparison, very
`little change in EDSS score was experienced in any treat-
`ment arm by patients with PPMS. Similarly, although no
`significant differences among treatment groups were found
`in time to progression assessed by Kaplan-Meier estimate
`for all patients, there was a trend toward a more favorable
`clinical response to cladribine than to placebo in the SPMS
`subgroup (figure 1); 33% of patients in the placebo group
`met the criteria for disease progression by the end of the
`double-blind phase, compared with 24% to 27% of
`cladribine-treated patients with SPMS.
`Exacerbations, steroid utilization, and hospitalizations
`did not differ among the three groups.
`Follow-up EDSS scores obtained after the 12-month
`double-blind phase, but before retreatment, are available
`
`4
`
`

`

`Table 2 Summary of MRI outcomes during double-blind phase of study: all patients
`
`MRI parameter
`
`Enhanced T1 lesions
`
`Proportion of patients with lesions (%)*"4
`Baseline
`
`Month 6
`
`Month 12
`
`Final evaluation
`
`Mean numberoflesions (SD)?
`Baseline
`
`Month 6
`
`Month 12
`
`Final evaluation
`
`Placebo
`Cladribine 0.7 mg/kg Cladribine 2.1 mg/kg
`
`
`
`n (%) or mean (SD) n(%)ormean (SD) pValue n(%)or mean (SD) p Value
`
`53 (38%)
`
`51 (33%)
`
`50 (82%)
`
`54 (31%)
`
`1.17 (2.23)
`
`0.78 (1.49)
`
`0.57 (1.10)
`
`0.58 (1.12)
`
`52 (33%)
`
`49 (12%)
`
`48 (10%)
`
`51 (10%)
`
`1.64 (4.43)
`
`0.17 (0.52)
`
`0.18 (0.40)
`
`0.12 (0.39)
`
`0.0169
`
`0.0131
`
`0.0080
`
`0.008
`
`0.007
`
`0.005
`
`50 (36%)
`
`52 (2%)
`
`48 (6%)
`
`52 (6%)
`
`1.10 (2.07)
`
`0.12 (0.85)
`
`0.09 (0.35)
`
`0.08 (0.34)
`
`0.001
`
`0.0017
`
`0.0009
`
`<0.001
`
`0.001
`
`0.001
`
`142.66 (302.15)
`
`283.82 (803.10)
`
`235.24 (777.94)
`
`Mean volumeoflesions in pL (SD)**4
`Baseline
`
`Month 6
`
`Month 12
`
`Final evaluation
`T2 lesions
`
`Mean lesion volume (mL) (SD)*"4
`Baseline
`
`Month 6
`
`Month 12
`
`Final evaluation
`
`Change from baseline tofinal evaluation®**
`Mean (SD)
`Median
`
`Percent change from baseline to final
`evaluation”*°
`
`78.67 (168.07)
`
`67.76 (119.65)
`
`78.11 (155.74)
`
`12.44 (44.35)
`
`10.94 (39.99)
`
`10.28 (38.83)
`
`0.008
`
`0.005
`
`0.008
`
`19.40 (137.18)
`
`<0.001
`
`6.36 (26.63)
`
`5.98 (25.85)
`
`0.001
`
`0.001
`
`12.90 (12.35)
`
`13.45 (12.77)
`
`13.13 (13.11)
`
`13.31 (13.00)
`
`13.03 (12.37)
`
`13.15 (12.09)
`
`12.62 (11.52)
`
`12.65 (11.96)
`
`0.41 (1.72)
`0.10
`
`—0.39 (1.70)
`—0.01
`
`9.91 (8.50)
`
`9.78 (8.60)
`
`9.79 (8.80)
`
`9.71 (8.56)
`
`—0.20 (1.13)
`—0.18
`
`0.872
`
`0.944
`
`0.868
`
`0.055
`
`0.155
`
`0.231
`
`0.180
`
`0.040
`
`—3.93 (14.80)
`—1.67 (14.98)
`1.81 (11.38)
`Mean (SD)
`
`
`0.144 —2.510.03 0.029
`1.53
`Median
`
`
`
`* Includes patients with both baseline and final evaluations.
`» Fisher’s exact test (two-sided significance).
`© Based on Wilcoxon’s (Mann-Whitney) rank sumtest.
`4 The final evaluation is the last evaluation for each patient up to month 12 during year 1.
`© Positive change indicates disease progression.
`
`through month 24 for a sizable cohort of patients, although
`cohort sizes became smaller as some patients entered re-
`treatment during the follow-up phase. Although mean
`EDSSscores increased over timein all treatment groups,
`scores for the follow-up period were also analyzed by pat-
`tern of disease. For patients with SPMS, mean changes in
`EDSS scores were somewhat more favorable with cladri-
`bine (0.2 and 0.3, respectively, for the 0.7-mg/kg and 2.1-
`mg/kg doses) compared with placebo (0.6) by 24 months.
`No difference was observed for patients with PPMS.
`Magnetic resonance outcomes.
`Proportion of patients
`with enhanced T1 lesions. At baseline, approximately
`35% of patients in each treatment group had enhanced T1
`lesions (figure 2, table 2). Whereas the proportion of pa-
`tients with enhanced T1 lesions remained nearly un-
`changed from baseline to final evaluation in the placebo
`
`group, the proportion of cladribine-treated patients with
`enhanced T1 lesions decreased significantly, to 10% in the
`0.7 mg/kg group (p = 0.0080) and 6% in the 2.1 mg/kg
`group (p = 0.0009). By final evaluation, there was a 70%
`reduction in the proportion of patients with enhanced T1
`lesions in the cladribine 0.7 mg/kg group and an 83% re-
`duction in this proportion in the cladribine 2.1 mg/kg
`group, compared with a reduction of 18% in the placebo
`group. The difference between the cladribine and placebo
`groups in the proportion of patients with enhanced T1
`lesions was statistically significant at month 6 (see figure
`2, table 2). It remained significant through month 18 for
`the 0.7 mg/kg dose and through month 24 for the 2.1 mg/kg
`dose (table 3).
`Subgroup analysis of the proportion of patients with
`enhanced T1 lesions by pattern of disease showed nosig-
`March(1 of 2) 2000 NEUROLOGY 54
`1149
`
`5
`
`

`

`PercentofPatientsWith
`
`EnhancedT,Lesions
`
`oao
`
`50
`(_] Placebo
`
`F272] Cladribine 0.7 mg/kg
`
`BS Cladribine 2.1 mg/kg
`
`
`
`
`
`31%
`
`[
`
`
`
`30 20
`
`ake o
`
`50
`n=53 52
`Baseline
`
`51
`
`49
`Month 6
`
`52
`
`52
`51
`54
`Final Evaluation
`
`nificant difference among treatment groups in patients
`with PPMS(data not shown). In patients with SPMS,how-
`ever, significantly smaller proportions of patients treated
`with either cladribine dose had enhanced T1 lesions at
`
`month 6 and the double-blind final evaluation, and those
`treated with 2.1 mg/kg maintained significant differences
`at follow-up months 18 and 24 (data not shown).
`Examination of the relationship between the status of
`patients with and without enhanced T1 lesions at baseline
`and their status at final evaluation showed that for pa-
`tients who presented without enhanced T1 lesions at base-
`line, new enhanced T1 lesions developed by final
`evaluation in 18% of placebo patients compared with 9%
`and 6%, respectively, of the low- and high-dose cladribine
`groups (NS). Moreover, for patients with enhanced T1 le-
`sions present at baseline, the treatment effect on enhanced
`T1 lesions at final evaluation was significantly greater in
`patients receiving 0.7 mg/kg (p < 0.02) and 2.1 mg/kg
`(p < 0.002) cladribine than in the placebo patients; these
`differences in treatment effect between the placebo group
`
`Figure 2. Proportion of patients with enhanced T1 lesions
`during the double-blind phase study. *p < 0.02 versus
`placebo. **p < 0.001 versus placebo. ***p < 0.0001 versus
`placebo.
`
`Table 3 Summary of MRI outcomes during post-double-blind follow-up: all patients
`
`
`MRIparameter
`n(%)ormean (SD)
`n(%)ormean(SD)
`pValue
`n(%)ormean(SD)
` p Value
`
`Placebo
`
`Cladribine 0.7 mg/kg
`
`Cladribine 2.1 mg/kg
`
`Enhanced T1 lesions
`
`Proportion of patients with lesions (%)""*
`Baseline
`
`Final evaluation
`
`Month 18
`
`Month 24
`
`Mean numberoflesions (SD)***""
`Baseline
`
`Final evaluation
`
`14 (36%)
`
`14 (36%)
`
`14 (36%)
`
`7 (24%)
`
`0.64 (1.04)
`
`0.62 (1.14)
`
`15 (32%)
`
`5 (10%)
`
`5 (11%)
`
`4 (11%)
`
`1.72 (4.56)
`
`0.13 (0.40)
`
`0.20 (0.67)
`
`0.0079
`
`0.0089
`
`0.1965
`
`0.004
`
`0.011
`
`16 (36%)
`
`2 (4%)
`
`1 (2%)
`
`0 (0%)
`
`1.09 (2.13)
`
`0.04 (0.21)
`
`0.07 (0.46)
`
`0.0002
`
`0.0001
`
`0.0014
`
`<0.001
`
`<0.001
`
`Month 18
`
`Month 24
`
`Meanvolumeoflesions (j1L)***"4
`Baseline
`
`Final evaluation
`
`Month 18
`
`Month 24
`T2 lesions
`
`Meanlesion volume (mL) (SD)**"*
`
`Baseline
`
`Final evaluation
`
`Month 18
`
`Month 24
`
`0.62 (1.37)
`
`1.17 (3.97)
`
`0.26 (0.82)
`
`0.182
`
`0.0 (0.00)
`
`0.001
`
`83.10 (160.33)
`
`298.11 (826.49)
`
`241.36 (816.41)
`
`75.87 (126.94)
`
`111.59 (351.47)
`
`10.94 (39.99)
`
`21.16 (90.58)
`
`168.83 (708.80)
`
`69.40 (236.50)
`
`0.003
`
`0.006
`
`0.238
`
`3.20 (15.10)
`
`4.42 (28.97)
`
`0.00 (0.00)
`
`<0.001
`
`<0.001
`
`0.001
`
`10.42 (8.80)
`
`10.47 (8.71)
`
`10.50 (8.75)
`
`10.75 (9.55)
`
`13.28 (12.49)
`
`12.87 (12.06)
`
`13.22 (12.21)
`
`12.41 (12.95)
`
`0.395
`
`0.379
`
`0.839
`
`10.34 (8.81)
`
`10.08 (8.87)
`
`9.91 (8.29)
`
`10.36 (8.83)
`
`0.825
`
`0.769
`
`0.945
`
`Percent change from baseline to Month 24°*
`
`3.74 (15.38) 1.02 (23.16)Mean (SD) —4,22 (17.55)
`
`
`
`
`
`* Includes patients with both baseline and final evaluations.
`> Fisher’s exact test (two-sided significance).
`© The final evaluation is the last evaluation of the double-blind phase.
`4 Based on Wilcoxon's (Mann-Whitney) rank sum test.
`* Positive change indicates disease progression.
`1150 NEUROLOGY 54 March(1 of 2) 2000
`
`6
`
`

`

`and cladribine groups were statistically significant at
`month 6.
`Volume and number of enhanced T1 lesions. The
`cladribine groups had approximately 90% reductions in the
`mean number of enhanced T1 lesions at month 6 and
`maintained 92% reductions through final evaluation, com-
`pared with 33% and 50% reductions in the placebo group
`at month 6 and final evaluation, respectively (see table 2).
`Thedifferences in the numbers of these lesions at the final
`
`evaluation between the placebo and cladribine 0.7 mg/kg
`groups (p = 0.005) and the placebo and cladribine 2.1
`mg/kg groups (p = 0.001) werestatistically significant, as
`were the differences at month 6. Compared with a 3%
`reduction in the mean number of enhanced T1 lesions in
`
`
`
`n= 48
`
`48
`Month 6
`
`45
`
`51
`
`46
`50
`Final Evaluation
`
`the placebo group at month 18 and a 77% increase at
`month 24, the cladribine groups maintained a 91% reduc-
`tion at month 18 (p < 0.001) and month 24 (p = 0.005, see
`table 3).
`The mean volume of enhanced T1 lesions also decreased
`from baseline in all three treatment groups during double-
`blind therapy, with greater reductions observed in the two
`cladribine groups (96% and 97%, respectively, for the low-
`and high-dose groups) compared with the placebo group
`(45%; see table 2). Differences between placebo and
`cladribine treatments in enhanced T1 lesion volume were
`statistically significant at each timepoint after baseline,
`with >90% reduction in both cladribine treatment groups
`at month 6. Compared with 34% and 70%increases in the
`volume of enhanced T1 lesions in the placebo group at
`months 18 and 24, respectively, patients receiving cladri-
`bine had a 95% reduction in volume at month 18 (p <
`0.001) and an 87% reduction at month 24 (p = 0.007, see
`table 3).
`Subgroup analysis of the volume and numberof en-
`hanced T1 lesions by